Aminoethanesulfonyl piperidine and pyrrolidine

ABSTRACT

STABLE, WATER-SOLUBLE AMINOETHANESULFONYL DERIVATIVES HAVING ANALGESIC ACTIVITY OR ANTILIPEMIC ACTION ARE DESCRIBED. THEY ARE PREPARED BY AMMONOLYSIS OF TH CORRESPONDING HALIDES, PREFERABLY UNDER HIGH PRESSURE IN THE PRESENCE OF A CATLAYST, OR BY DEACYLATION OF THE CORRESPONDING ACYLAMINO OR ACYLIMINO COMPOUND, OR BY NICOTINOYLATION OF AN AMINO COMPOUND.

United States Patent 3,709,889 AMINOETHANESULFONYL PIPERIDINE ANDPYRROLIDINE Shun-Ichi N aito, 35 Murasakino Kamitoridacho, Kita-ku,Kyoto, Japan No Drawing. Filed Mar. 9, 1970, Ser. No. 17,969 Claimspriority, application Japan, May 8, 1969, 44/ 35,435, 44/35,436,44/35,437 Int. Cl. C07d 29/34 US. Cl. 260-29335 3 Claims ABSTRACT OF THEDISCLOSURE Stable, water-soluble aminoethanesulfonyl derivatives havinganalgesic activity or antilipemic action are described. They areprepared by ammonolysis of the corresponding halides, preferably underhigh pressure in the presence of a catalyst, or by deacylation of thecorresponding acylamino or acylimino compound, or by nicotinoylation ofan amino compound.

The present invention relates to novel aminoethanesulfonyl derivativeshaving the formula:

and pharmaceutically acceptable non-toxic acid addition salts thereof,wherein or nicotinoylamino NHCO The compounds of the above Formula I areall novel and useful and have not heretofore been disclosed in theliterature. They are useful as pharmaceuticals, particularly asanalgesic drugs to relieve pain. Those in which X is piperidino orpyrrolidino exhibit antilipemic or cholesterol-lowering action and aretherefore useful in the treatment of atherogenesis. Furthermore, thecompounds of the present invention contain taurin as a fundamentalskeleton therein. Taurin is one of the essential amino acids exhibitingsurface active activity and the present compounds containing such amolecule as a skeleton do not decrease in their activity even when theyare subjected to detoxication such as an acetylation in vivo by oraladministration. This is a very characteristic property of all compoundsof this invention. In addition, the present invention compounds are oflow toxicity.

Another and important characteristic of these com pounds is that theyare very stable against humidity although all of them are comparativelysoluble or very soluble in water. Furthermore, their aqueous solutionsare stable, too. For example, only 2-10% of the compounds ice aredecomposed even when a 10% aqueous solution is stored at roomtemperature for one year. This is very advantageous for practicalpurposes, particularly when used in the form of an injectible solution.

The present compounds can be prepared in various ways. For example,compounds in which Y=NH can be produced by the reaction of XSO CH CH Z(II), wherein X is as defined above and Z is halogen, with ammonia.

The halogen Z may be chlorine, bromine, iodine, etc. and the use ofchlorine is preferred. The ammonia may be used as its own state, namelyas an ammonia gas or a liquid ammonia, or may be used as a solution,suspension, etc. in water and/or organic solvent; if desired, theammonia may be in its acid-addition salt form. The above ammonolysisreaction may be carried out under ordinary pressure but preferably iscarried out under high pressure in the presence of a catalyst. The useof such catalysts as NaI, Cu Cl NH.,I, etc. are preferred.

The halides used as starting materials in this method are novelcompounds forming .part of the invention. They may be prepared by thereaction of, for example, 2- pyridylamine, piperidine, cyclohexylamine,or pyrrolidine with haloethylsulfonyl halide.

The above method is illustrated by the following nonlimitative examples.

p 1 (X=pipen'dino, Y=NH TABLE 1 Reae- Temtion peratime, ture, Yield,Ammonia materials hours percent Catalyst used Anhydrous ammonia- 5 28NaI (0.45 g.).

Do. 5 100 33 C112C1z(1.0 g.). NfizCO: (10 g.) and 28% 8 30 CuzCl2(0.4g.).

Like reactions are carried out using (II) in which Z is bromine oriodine and it was found that the yields are somewhat lowered. Theabsence of catalysts are also found to decrease the yields.

In another embodiment, 10 g. of (H) (Z=Cl) are made to react withanhydrous ammonia or with aqueous ammonia and ammonium carbonate withheating in an autoclave in the presence of a catalyst, the mixture inthe autoclave is made acidic with hydrochloric acid, the precipitatesare removed by suction filtration, the filtrate is evaporated todryness, and the residue is recrystallized from ethanol to give thehydrochloride of the desired product. M.P. 173185 C. (decomposition withelfervescence). When this is further treated with an alkali, the freeproduct is obtained in high yield.

Example 2A (X=2-pyridylamino, Y=NH Ten (10) grams of ('II)(X=2-pyridyl=amin'o) are made to react with anhydrous ammonia or withaqueous ammonia and ammonium carbonate with heating in an autoclave inthe presence of a catalyst, the mixture is then made acidic withhydrochloric acid, precipitates are removed by suction filtration, thefiltrate is made alkaline with sodium carbonate, evaporated to drynessin vacuo,

the residue is well extracted with ethyl acetate, the extract isevaporated, and the residue is recrystallized from ethylene dichlorideto give the desired product. M.P. 13 7-- 140 C. Colorless crystals.

Analysis.-Calcd. for C7H11N3O2S (percent): C, 41.79;

materials, the yields are somewhat lowered. The absence of catalystsalso lowers the yield.

Manufacture of amino compounds by the ammonolysis of the correspondinghalide is given above. The desired product (I) where Y=NH may also beprepared by H, 5.47; N, 20.90. Found (percent): C, 41.88; H, 5.38; thedeacylation of the correspondmg acylammo or acyl- N, 21.03. irninocompounds. Thus the compound (I) where Details of the reaction are givenin Table 2.

TABLE 2 Reac- Tem- Yields, percent tion peratime, ture, Ammoniamaterials hours C. Z=Cl Z=Br Catalysts Anhydrous ammonia, g 5 100 86 NaI(0.45 g). Anhydrous ammonia, 20 g 5 100 92 80 C112Cl (1.0 g.). M 332 10g.) and 28% NH40H s 140 83 ouzolotod g). Anhydrous ammonia so 7s 1 120hours room temperature.

2 Not used.

Example 28 (X=2-pyridylamino, Y=NH Y=NH can be manufactured byhydrolysis or hydrazine Ten (10) grams of (H) O(=2 pyridylamino, ZZCDdecomposition of a compound having the general formula are made to reactwith anhydrous ammonia or with aque- XSO CH CH R (III) 01.15 P andammomum carbonate m an alltoclavp 9 wherein X is the same as definedabove and R is an acyl with heating in the presence of a catalyst, themnrture 1s amino limino group. then made acldlc Wm} hydrochionc acld thepheclpltates As acylamino groups, such aliphatic acylamino groups areremoved by.suct1n filtratlon i filtrate ls l as acetylamino,propionylamino, etc. and aromatic acylrated to dryness y and the reslqueis recrystallized amino groups as benzoylamino, nicotinoylarnino, etc.may from ethanol to gwe t hydrpciflonde of the desuied 30 advantageouslybe used. As acylimino groups, such groups Product. I 221-223 p f treatedas the phthalimino group are useful. These examples illusan al.kah glve.the free Product m hlgh i Whe.n thls trate the present invention but thepresent invention is not reaction 1s carried out with (II) where Z isbromlne or limited theretl lodme clawed y the absence a f i In thehydrolysis reaction, such known hydrolysis techproduct similarlyobtained through the yield is somewhat 3 niques as the use of acid,sodium, Sodium alcoholates, lowered- 0 alkali hydroxides, alkalicarbonates, etc. may advanta- Example 3 (X=cyclohexylamino orpyrrolidino, geously be used. The use of alkali hydroxides, particularlyY=NH the use of a concentrated solution of NaOH or KOH, is

most preferred.

(10) grams of (Z.=Cl) are made react 40 In deacylating by hydrazinedecomposition, hydrazine aniydmus i and hydrate is added to (III) inethanol or in methanol and ammomum carbonate m an alimclave. with i m tthen the mixture is treated with hydrochloric acid to presence a(fatalyst imxmre made and: w give the desired product. Other andmodified techniques hydrochloric acid, the precipitates are removed bysuction may also be applied advantageously filtration filtrate 1sevaPorated to dryness m The starting materials (III) used in this methodare and the residue is recrystallized from ethanol to give the alsonavel ccmpounds and may, for example, be Sym hydr?chlonde i the q g pthebfiltrate thesized by the reaction of Z-aminopyridine, piperazine,alkaline (PH a out 9) Wu so i car onate axtmcte cyclohexylamine, orpyrrolidine with the corresponding with ethyl acetate, the extract isevaporated, and the acylaminoethanesulfonyl halide residue isrecrystallized from chloroform to give the free This deacylafion methodis fl'lustratcd by the following product. Or, the filtrate is madealkaline with sodium nomll-mitative examples carbonate, evaporated todryness in vacuo, and the residue is recrystallized from water to givethe free product. Melt- Example 4A =P P 2) ing points and details of thereaction are given in Table 3 To 42 grams f n xzpiperidino,kzphthalimino) a d! Table b p yare added 300 ml. of 30 w./v. percentNaOH solution,

TABLE 3 the mixture is heated to reflux for 3 to 5 hours, allowed M MP fh h d to cool, then acidified with cone. HCl with ice-cooling, X k% 5 ,5e y andtnliade sligltitldy tahlkaltine witlit sodurnfcarlllaonate. fiThec o crys a s separae ere y are ept or urt er puri ca- Cyclohexylamm"ggggg 177-184 tion. The filtrate is extracted with ethyl acetate, theextract Pyrmlldlno (1b) ITO-173 o 320-2 2? C.(co or i 1 ed isevaporated, the resulting residue is combined with the an eomposepreviously obtained crystals, and the whole is repeatedly recrystallizedfrom chloroform to give 10 grams of the Products are wmrless crystalstitle product. Colorless needles, M.P. 205-207" (2.

TABLE 4 Arzalysis.Calculated for C H N O S (percent): C, Raw yields,43.75; H, 8.33; N, 14.58. Found (percent): C, 43.80; H,

g:- pelcem 8.28; N, 14.41. ur Ammonia materials hours o. (Is) (1b)Catalysts 'lhe same reactions are carried out using (HI) where Anhydrous5 mo 55 40 NM (M5 1s benzoylamino and acetylamino to give the disiredammonia (20 5 mo 56 41 0 c1 (10 t tle products in yields of 4 grams and2 grams, respecg y ga- 8 100 46 32 li -m; is tively. Similar productscan also be prepared by the use 28% H of (III) where Y is propionylaminoand nicotinoylammo groups.

The thus prepared compounds can, if necessary, be

When the above reactions are carried out using the corconverted to acidaddition salts by treatment with various responding bromide (Z=Br) oriodide(Z=I) as starting inorganic and organic acids. Such salts can alsobe used for the purpose of the purification of the products. Forexample, the crude product is once converted to the salt and the salt isreturned to the free amine which is obtained as a pure compound. One ofsuch embodiments is that the reaction product obtained above is treatedwith cone. HCl with ice-cooling, then made slightly acidic with sodiumcarbonate, the mixture is concentrated in vacuo to give a hydrochloride(M.P. 173-185 C.) of the product which is further treated with an alkalito give a purified product of MP. 205207 C.

Non-lirnitative examples of the hydrazine decomposition are as follows:

Example 4B (X=piperidino, Y=NH To 10 grams of (HI) (where X=piperidino,R=phthalimino) are added 100 ml. of ethanol and the mixture is heated toreflux for 2 to 3 hours with 1.6 g. of hydrazine hydrate (approx. 100%).The mixture is then adjusted to pH about 1 with HCl, heated on a steambath for 30 minutes more, filtered when hot to remove the separatedphthalic hydrazide, and the filtrate is cooled to give the hydrochlorideof the product. Or, this filtrate is made alkaline with Na CO evaporatedto dryness, the residue is extracted with warm methanol, the extract isstrongly cooled, filtered to remove the saturated mass, methanol isremoved from the filtrate, and the residue is repeatedly recrystallizedfrom chloroform to give the desired product. Colorless needles, M.P.205-7 C. Yield 1.8 grams. This is identical with the product obtained inExample 4A.

Example 5A (Y=NH To (III) (where R=phthalimino) is added 30 w./v.percent NaOH solution and the mixture is heated to reflux for 3 to 5hours. After cooling, this is acidified with cone. HCl with ice-cooling,adjusted to pH about 9 with Na CO and filtered to separate into thecrystals and the filtrate. The filtrate is extracted with ethyl acetateor with chloroform, the extract is evaporated, the residue is combinedwith the previously-obtained crystals, and the mixture is repeatedlyrecrystallized from water to give the desired product. Details of theabove reaction are given in Table 5.

Similar reactions are carried out using (III) (where R=benzoylamino andacetylamino) and the desired products are obtained. Details are given inTable 6.

Results of the elementary analysis of the thus prepared products aregiven in Table 7.

TABLE 5 Melting point of th products, Yields, Recrystallization X of(III) grams solvents 2-pyridylamlno 137-140 3.0 Ethylene dichlorideCyclohaxylamino 2 2.8 Water. Pyrrolidino 170-173 2.5 Do.

Colorized and decomposed.

The amount of the NaOH solution used is 80 ml. All the products arecolorless crystals.

ammo. Pyrrolidino-.- CsHuNzOzS 40.45 7.87 15.73 40.32 7.91 15.88

To (III) (R=phthalimino) is added about 5 to 8 volumes of ethanol, then1.1 times (III) molar amount of hydrazine hydrate (approx. is added, themixture is heated to reflux on a steam bath for about 3 hours withstirring, adjusted to pH about 1 with HCl, heated on a steam bath for 30minutes more, phthalic hydrazide is removed by filtration when themixture is still hot, and the filtrate is cooled to collect thehydrochloride of the product. This is purified by repeatedrecrystallization. Details are given in Table 8. Results of elementaryanalysis are given in Table 9.

Such hydrochlorides may also be obtained by the method as given inExample 5A provided that the amount of sodium carbonate used foralkalinization is so small that the mixture is kept still slightlyacidic.

amino.

Pyrrolidino-.- CcH15N202SC1- 33.49 6.98 13.02 33.52 6.81 13.23

These hydrochlorides can be converted to the free aminoethanesulfonylderivatives as given in Table 5 by the following method. Thus, they aredissolved in water, the solution is adjusted to pH about 9 with Na COevaporated to dryness, and the residue is recrystallized from water.When X is the Z-pyridylamino group, the product is to be preferablyrecrystallized from ethylene dichloride instead of water.

Manufacture of the product by ammonolysis of the corresponding halide orby deacylation of the corresponding acylamino or acylimino compound isgiven above in detail. The compound (I) where Y is nicotinoylamino canbe manufactured by nicotinoylation of the corresponding (I) where Y isNH It may be represented by the following reaction.

where X is the same as already defined.

Various known nicotinoylation techniques can be applied to the abovemethod. For examples, the use of an acid having a nicotinoyl group andits functional derivatives, such as an acid anhydride, ester, halide, ormixture thereof, are preferred. Such acid and its functional derivativesmay be in a form of a salt. The reaction may be carried out at roomtemperature or under warming or heating under ordinary or high pressureaccording to the kinds and amount of reactants. The starting material(IV) may also be in a form of a salt.

7 This method is illustrated by the following non-limitw tive examples.

Example 6A To 0.l mol of (IV) or its hydrochloride are added 100 to 200ml. of pyridine, the mixture is warmed for 1 hour with 0.1 mol ofnicotinic chloride hydrochloride (or allowed to stand at roomtemperature overnight and warmed for 1 hour more), pyridine isevaporated therefrom in vacuo, and the residue is repeatedlyrecrystallized from methanol or ethanol to give the hydrochloride of thedesired (V). To the residue after evaporation of pyridine is addedwater, the mixture is made alkaline (pH about 9) With Na CO thenevaporated to dryness in vacuo, and the residue is recrystallized fromwater to give the desired (V). Melting points and yields of them aregiven in Table 10. Elementary analysis data are given in Table 11.

When the crude product (V) is, for example, dissolved in methanol or inethanol and hydrochloric acid gas is bubbled therein or such alcoholicsolution is treated with hydrochloric acid, the correspondinghydrochloride is easily formed. Thus, the crude product (V) can bepurified via the hydrochloride.

8 Example 6B A mixture of 0.1 mol of starting material (IV), 0.1 mol ofnicotinic acid anhydride, and 100. ml of pyridine (anhydrous) is placedin a three-necked flask and stirred for 7 hours on a boiling water bath.Pyridine is evaporated therefrom in vacuo and the residue is madealkaline with a saturated aqueous solution of sodium carbonate to give ayellowish mass. The mixture is evaporated in vacuo to remove water andthe residue is repeatedly recrystallized from water to pure product (V).Such products are identical with the authentic samples alreadymanufactured by other methods. Details of the above reactions are givenin Table 12.

Example 60 A mixture of 0.1 mol of starting material (IV), 0.1 mol ofnicotinic acid, and 400 ml. of p-cymene is placed in a three-neckedflask equipped with a Water-remover and heated at 180-190 C. for about 6hours with stirring. The resulting water is removed by azeotropicdistillation. After cooling, the p-cyrnene is removed in vacuo. Theresidue is dissolved in the minimum volume of water, the solution ismade alkaline (pH about 9) with sodium carbonate, water is removed invacuo, and the residue is repeatedly recrystallized from water to givepure product (V) which is found to be identical with an authentic TABLE10 sample. Details are given in Table 12.

M.P. TABLE 12 Yield Ml. oi the f the a hydm Example 613 Example 60 redct 0 ct chl d p u pr 1 7), (V. ill)? Melting Melting X percent e point,Yield, point Yield, X percent percent 2- 1d lamlno.- 75 332-349 314-325cgg g 30 1 330 2 335.335 2-pyfldylflmill9 335-343 70 335-349 72Piperldtno 60 220-225 269-270 Cyclohqxylflmmon 378 63 D 330 g 3 3 5Plperldlno 222*225 65 221-225 63 Pyrrolidmo 2 330 50 1 330 71 X gigiiibhstered' 1 Carolina and blister-ed. 1 Confirmed by converting to thehydrochloride (M.P. 316-325 0. A11 the products are colorless crystals.lwlomedl TABLE 11 Analysis of (V), percent Analysis of (V. H01), percentCalculated Found Calculated Found Molecular X formula C H N C H N C H NC H N 2-pyridylamino. CIJHHN403S 50. 98 4. 58 18. 30 50. 91 4. 69 11. 2341. 16 4. 22 1 14. 78 41.30 4. 18 14. 95 Cyelohexylammo- CuHztNaOsS 64.02 6. 75 13. 50 53 95 6. 82 13. 66 48. 28 6. 32 12. 07 48. 40 6. 22 12.15 Piperidino CwHmNgOaS 52. 53 6. 40 14. 14 52. 76 6. 35 14. 21 46. 715. 99 12. 57 46. 68 6. 05 12. 68 Pyrrolidiuo C12H11N303S 50. 88 6. 0114. 84 60. 68 6. 98 14. 45. 00 5. 63 l3. 13 45. 11 5. 5O 13. 32

l Dihydrochlorlde.

The use of nicotinic chloride instead of nicotinic chloridehydrochloride has no influence on the yield of the product. Thecondensation reaction of starting material (IV) or its acid additionsalt with nicotinic halide proceeds in water or in various organicsolvents as well as in pyridine. It has also been confirmed that thereaction proceeds advantageously when a small amount of alkali orpyridine is added to water or other organic solvents.

For example, 500 ml. of ethyl acetate are added to 0.1 mol of thestarting material (IV) or its hydrochloride, 0.1 mol of nicotinic acidchloride hydrochloride is added thereto, the mixture is heated to refluxon a steam bath for 3 hours, ethyl acetate is evaporated from thereaction mixture, and the resulting yellowish white solid isrecrystallized from ethanol or from methanol to give the hydrochlorideof the desired compound (V). Or, the above solid is dissolved in a smallamont of water, the solution is made alkaline (pH about 9), with Na COwater is evaporated therefrom in vacuo, and the residue isrecrystallized from water to give pure product (V). Yields of theproducts in the above reactions are almost the same as those given inTable 10.

The use of nicotinic acid anhydride and nicotinic acid instead ofnicotinic acid chloride (hydrochloride) has also been carried out. Someembodiments are given in the following Examples 6B and 6C.

The present reaction may also be carried out in the presence of acatalyst.

The nicotinoylaminoethanesulfonyl derivatives (V) possessing a nicotinicpyridine ring in the skeleton and the nitrogen atom in said ring showbasicity. Therefore, the resulting (V) may, if desired, be made to reactwith various inorganic and organic acids to convert to the correspondingacid-addition salts. Thus, not only such inorganic salts as thehydrochloride but also such organic salts as the fumarate, flavanate,tartrate, etc. may be manufactured and, for the purpose of purificationof the product (V), such salts can advantageously be applied. Forexample, conc. hydrochloric acid is added to (V) and the mixture isevaporated to dryness in vacuo or HCl gas is introduced into amethanolic or ethanolic solution of (V) to give the hydrochlorideeasily. The resulting hydrochloride is recrystallized from methanol orethanol so that purification is easily carried out.

What is claimed is:

1. A compound of the formula:

wherein X is piperidino or pyrrolidino, or a pharmaceutically acceptablenontoxic acid addition salt thereof.

10 2. The compound which is OTHER REFERENCES J. Org. Chem, vol. 12:295-297 (1947), Mead et a1. J. Chem. Soc., 2348-2351 (1926), Ing et a1.

The which is 5 HENRY R. JILES, Primary Examiner N SO,CH,CH, NH, S. D.WINTERS, Assistant Examiner US. Cl. X.R.

References Cited 260326 82 2948 F 556 A 291 543 R 3263 326' UNITEDSTATES PATENTS 10 424-267, 274, 264, 263, 321 3,235,593 2/1966Friedlander 260556 A

